A5002916676- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Cell death mechanisms and regulation
- Autophagy in Disease and Therapy
- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Chronic Lymphocytic Leukemia Research
- Pancreatic function and diabetes
- Phagocytosis and Immune Regulation
- Renal Diseases and Glomerulopathies
- Renin-Angiotensin System Studies
- Malaria Research and Control
- Pharmacology and Obesity Treatment
- Liver Disease Diagnosis and Treatment
- Glycosylation and Glycoproteins Research
- Cancer-related Molecular Pathways
- Protein Hydrolysis and Bioactive Peptides
- Metabolism and Genetic Disorders
- HIV/AIDS drug development and treatment
- Chemotherapy-induced cardiotoxicity and mitigation
- Hematological disorders and diagnostics
- Asthma and respiratory diseases
- Allergic Rhinitis and Sensitization
- Lipid metabolism and biosynthesis
- Biochemical effects in animals
Takeda (United States)
2014-2021
UCB Pharma (United Kingdom)
2013-2019
Millennium Engineering and Integration (United States)
2002-2016
Takeda (Japan)
2016
In-Q-Tel
2016
University of Minnesota
2011
University of Iowa
2011
Ghent University
2009
Mayo Clinic
1995
University of Alberta
1989-1992
Human angiotensin-converting enzyme-related carboxypeptidase (ACE2) is a zinc metalloprotease whose closest homolog angiotensin I-converting enzyme. To begin to elucidate the physiological role of ACE2, ACE2 was purified, and its catalytic activity characterized. proteolytic has pH optimum 6.5 enhanced by monovalent anions, which consistent with ACE. increased ∼10-fold Cl− F− but unaffected Br−. screened for hydrolytic against panel 126 biological peptides, using liquid chromatography-mass...
The proteasome was validated as an oncology target following the clinical success of VELCADE (bortezomib) for injection treatment multiple myeloma and recurring mantle cell lymphoma. Consequently, several groups are pursuing development additional small-molecule inhibitors both hematologic solid tumor indications. Here, we describe MLN9708, a selective, orally bioavailable, second-generation inhibitor that is in phase I development. MLN9708 has shorter dissociation half-life improved...
The mammalian 26S proteasome is a 2500 kDa multi-catalytic complex involved in intracellular protein degradation. We describe the synthesis and properties of novel series non-covalent di-peptide inhibitors used on capped tri-peptide that was first identified by high-throughput screening library approx. 350000 compounds for ubiquitin–proteasome system cells. show these are entirely selective β5 (chymotrypsin-like) site over β1 (caspase-like) β2 (trypsin-like) sites 20S core particle...
Angiotensin-converting enzyme-related carboxypeptidase (ACE2) is a recently identified zinc metalloprotease with activity that was using our genomics platform. We implemented rational design approach to identify potent and selective ACE2 inhibitors. To this end, picomolar inhibitors of were designed synthesized.
The clinical success of the first-in-class proteasome inhibitor bortezomib (VELCADE) has validated as a therapeutic target for treating human cancers. MLN9708 is an investigational that, compared with bortezomib, improved pharmacokinetics, pharmacodynamics, and antitumor activity in preclinical studies. Here, we focused on evaluating vivo MLN2238 (the biologically active form MLN9708) variety mouse models hematologic malignancies, including tumor xenograft derived from lymphoma cell line...
Multiple pathways have been proposed to explain how proteasome inhibition induces cell death, but mechanisms remain unclear. To approach this issue, we performed a genome-wide siRNA screen evaluate the genetic determinants that confer sensitivity bortezomib (Velcade (R); PS-341). This identified 100 genes whose knockdown affected lethality and structurally diverse set of other inhibitors. A comparison three lines revealed 39 were commonly linked death. We causally bortezomib-induced death...
The Plasmodium proteasome represents a potential antimalarial drug target for compounds with activity against multiple life cycle stages. We screened library of human inhibitors (peptidyl boronic acids) and compared activities purified P. falciparum 20S proteasomes. chose four hits that potently inhibit parasite growth show range selectivities inhibition the cell lines. was selected resistance in vitro to clinically used inhibitor, bortezomib, whole genome sequencing applied identify...
We have identified short N,C-capped peptides that selectively inhibit the proteasome of malaria-causing pathogen Plasmodium falciparum. These compounds are highly potent in culture with no toxicity host cells. One cyclic biphenyl ether compound inhibited intraerythrocytic growth P. falciparum an IC50 35 nM, and we show even a pulse treatment this peptide induced parasite death due to inhibition. represent promising new antimalarial agents target essential proteasomal machinery without toward host.
Management of severe asthma remains a challenge despite treatment with glucocorticosteroid therapy. The majority studies investigating disease mechanisms in treatment-resistant have previously focused on the large central airways, very few utilizing transcriptomic approaches. small peripheral which comprise airway surface area, remain an unexplored area and were targeted for global epithelial gene expression profiling this study. Differences between airways evaluated using analysis...
Significance Here, we describe inhibitors of the Plasmodium proteasome, an enzymatic complex that malaria parasites rely on to degrade proteins. Starting from developed treat cancer, derivatives were designed and synthesized with aim increasing potency against proteasome decreasing activity human enzyme. Biochemical cellular assays identified compounds exhibit selectivity potency, both in vitro vivo, at different stages parasite’s lifecycle. Cryo-electron microscopy revealed bind a...
<b><i>Background:</i></b> Tubulointerstitial fibrosis is a key feature of chronic kidney diseases leading to renal failure. It characterised by the infiltration fibroblasts and aberrant accumulation extracellular matrix (ECM) proteins, which are associated with progressive loss function. Integrins play major role in fibrosis, but mechanisms through they do this not fully understood. <b><i>Objective:</i></b> Using complex cell system, we test...
1. A rapid extraction and purification scheme was designed for the recovery of [3H]diacylglycerol formed during assay phosphatidate phosphohydrolase. 2. The importance removing polyvalent cations, particularly Ca2+, from other reagents used in phosphohydrolase activity demonstrated. This achieved mainly by treating with a chelating resin adding 1 mM-EGTA mM-EDTA to assays. 3. dialysed samples soluble microsomal fractions rat liver very low. 4. Addition optimum concentrations MgCl2 resulted...
To investigate whether clinically relevant levels of epigallocatechin gallate (EGCG, a component green tea) or vitamin C (ascorbic acid) could antagonize bortezomib antitumor activity in CWR22 human prostate xenograft tumors.The pharmacokinetics (PK) EGCG and ascorbic acid were determined immunocompromised mice compared with concentrations measured PK studies dietary supplements. Antitumor combination was using several dosing regimens to evaluate different target plasma acid.Bortezomib dosed...
Testosterone (40-300 microM), oestradiol (20-500 progesterone dexamethasone (10 nM-1 microM) and corticosterone (1-10 activate glycogen phosphorylase rapidly when added directly to hepatocytes. The activation of was concentration-dependent occurred after 10 min for dexamethasone, 30 testosterone 60 progesterone. This rapid effect does not appear be dependent on a stimulation protein synthesis, it is independent an increase in cyclic AMP, diminished by the presence ornithine decarboxylase...
In non-clinical studies, the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor lines vitro. contrast, antitumor activity xenograft tumors is model-dependent, with some showing no response to ixazomib. this study we examined factors responsible for sensitivity or resistance using mouse models. A survey 14 non-small lung cancer (NSCLC) and 6 colon xenografts showed striking relationship between KRAS genotype; wild-type (WT) were more sensitive than harboring...
The proteasome inhibitor bortezomib is associated with the development of peripheral neuropathy in patients, but mechanism by which can induce not fully understood. One study suggested that off-target inhibition proteases other than proteasome, particularly HtraA2/Omi, may be underlying neuropathy. same also concluded carfilzomib, a second less patients bortezomib, showed no HtrA2/Omi. goal work described here was to determine whether either inhibitors truly affected HtrA2/Omi activity. A...
The lipase inhibitors, Triton WR‐1339 and tetrahydrolipstatin, were incubated with rat hepatocytes. increased the recovery of triacylglycerol in hepatocytes incubation medium by 31% 38%, respectively. Tetrahydrolipstatin decreased accumulation newly synthesized, total medium. This compound might be useful determining mechanisms involved intracellular metabolism secretion very low density lipoproteins.
Inhibition of the proteasome by covalent inhibitors is a clinically proven anti-cancer therapy. We report here that dipeptides with P3 neopentyl Asn residue are potent, reversible, non-covalent selective for chymotryptic activity 20S in vitro and cells. The X-ray structure compound 20 complex yeast reveals importance hydrophobic bonding interactions group within S3 binding pocket β5 sub-unit. Four compounds show comparable potencies to boronic acid panel assays.
1. The effects of D-fenfluramine were studied in the JCR:LA-corpulent rat that is grossly obese, hyperphagic, hyperlipidaemic, hyperinsulinaemic and atherosclerosis-prone. 2. Daily doses 1, 2.5 5 mg kg-1 produced sustained decreases body weight food intake over a period 30 days 6 month old female rats fed ad libitum. This was accompanied by circulating concentrations glucose, triacylglycerol, free cholesterol insulin. 3. Food restriction imposed meal feeding also decreased triacylglycerols,...
Urine concentration and renal clearance of free sulphadimidine are diminished in patients with impaired function. Although accumulation prolonged administration has not been demonstrated, it seems likely that this would occur. Other sulphonamides which effective at lower concentrations less easily conjugated may be preferable poor function, particularly if given combination trimethoprim. Sulphadimidine can administered intraperitoneally a up to 100 μg/ml for 4 5 days without undue side effects.
Oleate, linoleate, linolenate, arachidonate and eicosapentaenoate, but not myristate, palmitate stearate, stimulated glycogen phosphorylase activity by 2-8-fold when added to cultured rat hepatocytes. Addition of BSA or Ca2- the incubation medium decreased stimulating effects unsaturated fatty acids. The combination oleate with corticosterone, testosterone estradiol produced synergistic stimulations activity. stimulation linolenate was inhibited staurosporine sphingosine. Staurosporine (80...